Cytokines and lymphokines, such as interferons, GM-CSF, IL-1, IL-2, IL-3 , IL-4, IL-5, IL-6 and IL-7 have been shown to have different activities in modulating the immune response. Hormones and growth factors also have modulating effects on cells of the immune system and thus can modulate the immune response. Interferons , IL- 1 and IL-2 augment proliferation and differentiation of antigen or mitogen stimulated T cells. They also stimulate B cells to grow and generate antibody responses to anti gels once activated, B cells have been shown to express IL-2 receptors. A number of synthetic and recombinant lymphokines (Nencioni et al., J. Immunol. 139:800-804 (1987); Kronheim et al., U.S. Pat. No. 4,801,686; Tagliabue et al. , U.S. Pat. No. 4,774,320; Fernandes et al., U.S. Pat. No. 4,604,377) have been shown to stimulate immune functions. However, inflammatory and toxic effects often accompany immunotherapeutic administration of cytokines or lymphokines to an organism. In addition, these molecules generally have short half lives.
Certain cytokines and lymphokines have been shown to have adjuvant activity thereby enhancing immune response to an antigen. For example, Nakamura et al. demonstrated that interferon-gamma induced a two- to five-fold enhancement of antibody formation to several antigens. Nakamura et al., Nature 307:381-382 (1984). Interleukins have also been shown to enhance an immune response to antigens. Nencioni et al., J. Immunol. 139:800-804 (1987); Howard et al., EP285441.
The stimulation of antibody response to poorly immunogenic thymus-independent antigens such as polysaccharides has been accomplished in recent years by the covalent coupling of polysaccharides onto a strong thymus-dependent protein antigen. A number of proteins such as diphtheria toxoid, tetanus toxoid and a non-toxic variant of diphtheria toxin, CRM.sub.197 are used as carriers for polysaccharides. The immune response is highly variable depending on the type of protein used as carrier.
A number of conjugates have been previously described for stabilizing and solubilizing proteins such as lymphokines. Moreland and Nitecki (U.S. Pat. No. 4,745,180May 17, 1988) describe a pharmaceutical composition comprising .beta.-interferon interleukin-2 or an immunotoxin which is covalently conjugated to a heparin fragment. The conjugate provides a means for solubilizing the protein which is essentially insoluble in its unconjugated form.
Schmidt et al. (U.S. Pat. No. 4,772,685, Sep. 20, 1988) describe immunogenic conjugates of IL-1 derived peptides to a high molecular weight carrier protein. Conjugates of IL-2 or interferon and a water soluble polymer (polyethylene glycol) have been described (Katre and Knauf, U.S. Pat. No. 4,766,106, Aug. 23, 1988 and WO8700056 Jan. 15, 1987). Similarly, Carman (EP183503 Jun. 4, 1986) describes conjugates of interferon or IL-2 linked to a water soluble polymer for sustained release of the lymphokine. For background on hormones and growth factors and their receptors see, for example, Hill, D. J., J. Reprod, Fertility 85: 723-734 (1989); Roupas et al., Mol. Cell. Endocrinol. 61:1-12 (1989).